Parkinson's disease (PD), Alzheimer's disease (AD) and Lewy Body disease (LBD) are the most commonly found neurodegenerative disorders in the elderly population. Although their incidence continues to increase thus creating a serious public health problem, to date these disorders are neither curable nor preventable. Previous studies have shown that cognitive alterations seen with these disorders are most often associated with synaptic damage and that injury to the synapse might be associated with altered function of synaptic proteins. Among them, recent studies have pointed to α-synuclein, also known as the precursor of the non-Aβ component of Alzheimer's disease amyloid (NACP) as a major player in the pathogenesis of these diseases.
The neurodegenerative process in Parkinson's disease and Alzheimer's disease is characterized by extensive loss of selected neuronal populations accompanied by synaptic injury, astrogliosis and pathological hallmarks such as amyloid plaques, neurofibrillary tangles and neutrophil thread formation in Alzheimer's disease and the intraneuronal inclusions called Lewy bodies in Parkinson's disease. Parkinson's disease belongs to a heterogenous group of disorders presenting with parkinsonism and Lewy Body formation and which has been denominated Lewy body disease. Although the mechanisms triggering cell death and synaptic damage are unclear, the prevailing view is that neurodegeneration might result from gain of a toxic property of specific neuronal cell proteins, such as α-synuclein (in Parkinson's disease) and amyloid precursor protein (APP) (in Alzheimer's disease). In this regard, APP has been proposed to be centrally involved in Alzheimer's disease pathogenesis because mutations within this molecule are associated with familial forms of Alzheimer's disease, proteolytic products of APP processing abnormally accumulating in brains of Alzheimer's disease patients and overexpression of a mutant form of APP in transgenic mice mimics several aspects of Alzheimer's disease.
α-Synuclein, which belongs to a larger family of molecules including β- and γ-synuclein, is a 140 amino acid synaptic protein which is a precursor of the 35 amino acid amyloidogenic molecule non-amyloid component (NAC). α-Synuclein has been implicated in Parkinson's disease because it is abundantly found in Lewy Bodies, its overexpression in transgenic mice leads to Parkinson's disease-like pathology, and mutations within this molecule are associated with familial Parkinson's disease. While the precise mechanism by which α-synuclein and APP might interact during events leading to neurodegeneration are unclear, several studies support the contention that α-synuclein is involved in Alzheimer's disease because it abnormally accumulates in synapses and dystrophic neurites surrounding the plaques in Alzheimer's disease brain and NAC is present in amyloid plaque cores and promotes Aβ aggregation. Moreover, other studies have shown that both α-synuclein and Aβ aggregate under similar experimental conditions, and in familial Alzheimer's disease and Down's syndrome there is formation of α-synuclein-immunoreactive Lewy Bodies. Furthermore, a combined form of Parkinson's disease and Alzheimer's disease has also been associated with the widespread formation of α-synuclein-immunoreactive Lewy Bodies. Taken together, these studies support the possibility that interactions between α-synuclein and APP might lead to enhanced amyloidogenesis and neurodegeneration in disorders such as Parkinson's disease and Alzheimer's disease.
Several studies have suggested that neurons may be able to develop protective strategies against the neurotoxic effects of amyloid. For example, in neurodegenerative disorders associated with trinucleotide repeats, such as Frederick's ataxia, Myotonic dystrophy and Huntington's disease, formation of intraneuronal inclusion bodies might be protective, because the toxic proto-fibrils are sequestered. Similarly, in Parkinson's disease and Alzheimer's disease, is has been suggested that proto- rather than mature fibrils are neurotoxic. In this context, it is possible that the balance between amyloidogenic and anti-amyloidogenic molecules regulates neuronal survival. It is hypothesized that β-synuclein, the non-amyloidogenic homologue of α-synuclein, which naturally lacks the NAC domain, may inhibit amyloidogenesis and neurodegeneration. β-Synuclein is similar to α-synuclein in that it is abundantly expressed in the central nervous system, whereas γ-synuclein is expressed mainly in the peripheral nervous system. The relationship between α-synuclein and β-synuclein is strikingly similar to that of APP and its related protein APLP2 in that APLP2 is highly homologous with APP except for its Aβ domain and that it is non-amyloidogenic.
Human α-synuclein belongs to a larger family of synuclein proteins encoded by a gene on chromosome 4 and is highly abundant in the presynaptic terminals throughout the central nervous system (CNS). While the precise function of the synuclein superfamily of peptides is still unknown, several lines of evidence suggest potential roles in synaptic function and neural plasticity. Synelfin is the avian homologue to α-synuclein and PNP14 is the bovine homologue to human and murine β-synuclein, a phosphoprotein encoded by a gene on chromosome 5. More recently, γ-synuclein was isolated as a D3 synuclein-like molecule which was expressed predominantly in peripheral sympathetic neurons. γ-Synuclein was later cloned from the EST library as the breast cancer specific gene (BCSG1) whose expression was observed in invasive types of breast cancer. Human α-synuclein was originally isolated from plaques of Alzheimer's disease brains as a 19-kD protein precursor of the highly hydrophobic 35-amino acid metabolite, non-amyloid component (NAC) of plaques. The NAC peptide can self-aggregate into fibrils and induces aggregation of the β-amyloid peptide.
Applicants seeks to establish that abnormal synuclein expression is involved in the pathogenesis of the neurodegenerative disorders Alzheimer's disease, Parkinson's disease and Lewy Body disease as well as determining the levels of α-, β-, and γ-synuclein mRNA in the brains of Lewy Body disease, Alzheimer's disease and Parkinson's disease in correlation with clinical and pathological indicators of these diseases.